1. Field of the Invention
The present invention relates to the field of radiopharmaceutical synthesizers. More particularly, the invention relates to an automated system for purifying radioisotopes and formulating radiopharmaceuticals having replaceable cassettes and methods of its use.
2. Description of Related Art
Non-invasive medical imaging techniques such as Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) have been experiencing explosive growth due to advances in functional imaging technology. New molecular imaging targets for diagnosis and therapy have been developed to visualize disease states and pathological processes without surgical exploration of the body. In particular, targeted radiopharmaceuticals offer promising capabilities for the non-invasive assessment of the pathophysiology of diseases. However, radiopharmaceuticals suitable for clinical use have been limited, which has led to the recent development of new radiopharmaceuticals with improved sensitivity, specificity, signal-to-background ratio and biodistribution.
One factor that has limited the number of suitable radiopharmaceuticals available relates to the relatively short half lives of the radioisotopes used in radiopharmaceuticals. Short half-lives are required to provide a strong signal during imaging and to subsequently limit the patient's exposure to radioactive materials after the imaging is completed.
To date, the most commonly used radioisotopes have been those derived from a cyclotron. Cyclotrons accelerate charged particles to high speeds causing the charged particles to collide with a target and thereby produce radioisotopes. While effective, cyclotrons are large and costly systems. As a result, many medical imaging facilities must obtain their radioisotopes from cyclotron facilities that are significant distances away. The time that it takes to synthesize radiotracers from the radioisotopes and deliver them to a medical imaging facility necessitates that the radioisotopes used have somewhat longer half lives than might otherwise be ideal.
An attractive alternative to obtaining radioisotopes from cyclotrons is available. This alternative involves the use of small radioisotope generators that are far more economical than cyclotron facilities. These generators are based on a parent-daughter (P/D) nuclidic pair wherein a relatively long-lived parent isotope decays to a short-lived daughter isotope suitable for imaging. The parent isotope, which is produced at a cyclotron facility, can be shipped to a clinical site and is the source from which the daughter isotope may be readily eluted. Generators of this type are smaller and relatively inexpensive and therefore more easily affordable for use on-site at a medical imaging facility.
One example of such generators are the 68Ge/68Ga generators. 68Ge is the parent nuclide and has a half-life of 271 days. 68Ge decays to produce the positron-emitting 68Ga, which has a half-life of 68 minutes. Periodically 68Ga can be selectively eluted from the generator using an acidic solution. The eluted radioisotope must then be purified and formulated as a radiopharmaceutical appropriate for use as a radiotracer.
The short half-life of 68Ga permits applications with suitable radioactivity while maintaining patient dose to an acceptable level. Furthermore, 68Ga3+ cation can form stable complexes with many ligands containing oxygen and nitrogen as donor atoms. This makes 68Ga suitable for complexation with various chelators and macromolecules. Over the last three decades, several 68Ge/68Ga generators have been developed that provide a high yield of 68Ga and relatively low breakthrough of 68Ge. While some purification of the 68Ga obtained from such generators may be required, the 68Ga that is produced is highly suitable for the formulation of radiopharmaceuticals.
Radioisotope purification and radiopharmaceutical formulation require intricate handling of radioactive materials, fast reaction times, ease of synthesis and reproducible results. Synthesis of radiotracers is therefore challenging for several reasons: 1) the synthesized radiopharmaceuticals must meet strict sterility and pyrogenicity requirements which must be validated from batch to batch; 2) the system must be highly reproducible from batch to batch, demonstrating suitable radiochemical yield, radiochemical purity, pH and specific activity; 3) the synthesis time must be fast when dealing with radionuclides with a short half-life or the nuclides will lose their utility as radiotracers; and 4) the purification and synthesis equipment and protocols used must afford maximal protection for radiochemists doing the purification and synthesis by minimizing their exposure to the highly radioactive materials being handled. The Food and Drug Administration (FDA) permits radiopharmaceuticals produced under well-controlled conditions in central commercial facilities to be distributed to local clinics where they are administered. In addition, radionuclide generator systems used in well-controlled facilities have gained FDA acceptance and have a long history of successful clinical application. The clinical application of generator-based radiotracers is therefore mainly limited only by the half-life of produced (daughter) radioisotopes and the choices of imaging agents.
Currently, there is no commercially available synthesizing apparatus for 68Ga-based PET imaging agents. The only commercially available automated synthesizer for generator-based PET imaging is the 62Cu generator (62Zn/62Cu). However these systems are designed only to synthesize a single type of radiopharmaceutical, they do not provide mechanisms that control or monitor the progress of the synthesis nor do they provide interchangeable cassettes or cartridges for rapid and convenient cleaning of the system.
Fully-automated systems for radiopharmaceutical synthesis have been developed for synthesis of radiopharmaceuticals from cyclotron-derived radioisotopes such as the GE TRACERlab MX line of products. Such devices have not been designed however for use with generator-derived radioisotopes such as 68Ga. These devices are small enough to fit in a standard laboratory hot cell and in some cases make use of replaceable cartridges that permit the user to rapidly replace between runs the components that were in contact with radioactive materials. Generally, however, automated systems of this type do not purify radioisotopes because purification is generally not required for cyclotron-derived radioisotopes. Also each device is customized to formulate one particular type of radiopharmaceutical and is not designed to be adapted by the user to formulate other types of radiopharmaceuticals, even those that use the same radioisotope.
Meyer et al. (Meyer, G. J., H. Macke, J. Schuhmacher, W. H. Knapp and M. Hofmann. 68Ga-labelled DOTA-derivatised peptide ligands, Eur. J. Nucl. Med. Mol. Imaging (2004) 31:1097-1104 (2004)) discloses a semi-automated system for purification of 68Ga and synthesis of a single type of 68Ga radiopharmaceutical, DOTA-derivatized peptide ligands. The disclosed system permits monitoring and on-line control of most, but not all steps in the process. Furthermore the disclosed system does not provide any mechanism for adapting the system to the purification of other radionuclides or the synthesis of other radiopharmaceuticals. The disclosed system also does not eliminate dead volume loss nor does it provide for a rapid and simple mechanism for replacing parts in contact with the radionuclide or radiopharmaceutical between syntheses.
WO 2005/057589 discloses systems and methods for synthesizing oil-soluble and water-soluble radioisotopic agents. Automated systems are disclosed for preparing radioisotopes and subsequently synthesizing radiotracers from those isotopes. The automated systems comprising valve assemblies coupled to a control unit. The application does not, however, disclose a mechanism for the rapid and simple replacement of parts in contact with radioactive materials between syntheses.
Therefore there is a need in the art for fully-automated devices that purify generator-produced radioisotopes and formulate radiopharmaceuticals from the purified radioisotopes. Ideally, the required device would be easily adaptable for use with different radioisotopes and for the formulation of different radiopharmaceuticals. The ideal device would also be designed to have replaceable parts that could be exchanged easily between runs and would minimize a user's exposure to radioactive materials during the preparation of purified radioisotopes or radiopharmaceuticals.